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Development of a non-invasive transdermal continuous glucose monitor for preterm neonates


de Courten, Damien. Development of a non-invasive transdermal continuous glucose monitor for preterm neonates. 2016, ETH Zürich, Faculty of Science.

Abstract

Today, glucose is still measured invasively at the Neonatal Intensive Care Unit (NICU)by sampling blood of extreme and very preterm neonates only every few hours because of the unavailability of accurate non-invasive and continuous monitoring technology dedicated to these very sensitive patients. Yet, there is an essential and unmet need for such a technology at the NICU because severe hypoglycemia and hyperglycemia increases preterm neonates morbidity and leads to impaired brain development. Moreover, blood sampling is a source of infection and repeated pain for premature infants. Consequently, for preventing impaired brain development in extreme preterm neonates in addition to reducing pain, infection risks, and costs for hospitals, we developed a continuous, non-invasive, transdermal, auto-calibrating probe monitoring glucose from passive diffusion. The skin of extreme and very preterm neonates is highly permeable allowing the largely unhindered passage of glucose. Hence glucose passively diffuses through the skin to a sensor where its concentration is measured. The measured diffusion rate is proportional to blood glucose. Yet, it depends on the diffusion resistance of the skin, which varies as a function of location, skin type, biophysical and biochemical properties of the skin as well as the age of the infant. We demonstrated the theoretical feasibility of two different approaches measuring glucose transdermally without calibration to take into account the skin permeability. We discarded the first approach consisting of probe with a non-responsive membrane and a very shallow diffusion chamber probed by evanescent wave spectroscopy for fast diffusion reaching equilibrium with blood glucose. The reasons were the insufficient in-vitro accuracy and limitations in miniaturization potential of NIR evanescent wave spectroscopy. Therefore we selected the promising second approach of measuring blood glucose transdermally with differential microdialysis measurement for auto-calibration. This novel noninvasive principle measures two different glucose diffusion rates with two distinct known membrane permeabilities. Therefore, it allows determining the two unknowns, the blood glucose and the skin permeability to glucose. Following this principle, we designed, manufactured, and characterized a microdialysis probe with two separate diffusion chambers, each with a distinct membrane, under the assumption that the skin permeability is locally constant. This probe is dedicated to NICU. It benefits from the properties of its Amphiphilic Polymer Co-Network (APCN) membranes with permeabilities fine-tuned to an acceptable measurement error and advantageous fluidics haracteristics. In addition, we designed, fabricated, and characterized an inline continuous micro-fluorimeter implementing the gold standard of glucose concentration measurement with hexokinase. This fluorimeter renders the microdialysis probe continuous with a small delay of one minute only. Onto a single chamber microdialysis probe, we further bonded an APCN membrane made light responsive with the copolymerization of spiropyran into the membrane hydrophilic nanophase. We demonstrated a significant microdialysate extraction fraction switch in response to UV or visible light illumination. Unfortunately, we showed that this switch is probably only indirect and is induced by temperature changes. This membrane would not allow implementing our non-invasive principle, but showed that other type of membranes with the correct mechanism could do it. But this approach is probably not necessary with the simpler parallel microdialysis chambers design. To the best of our knowledge, this is the first time that such a non-invasive, continuous, auto-calibrated measurement principle is proposed for blood glucose and also implemented with a probe dedicated to extreme and very preterm neonates.

Today, glucose is still measured invasively at the Neonatal Intensive Care Unit (NICU)by sampling blood of extreme and very preterm neonates only every few hours because of the unavailability of accurate non-invasive and continuous monitoring technology dedicated to these very sensitive patients. Yet, there is an essential and unmet need for such a technology at the NICU because severe hypoglycemia and hyperglycemia increases preterm neonates morbidity and leads to impaired brain development. Moreover, blood sampling is a source of infection and repeated pain for premature infants. Consequently, for preventing impaired brain development in extreme preterm neonates in addition to reducing pain, infection risks, and costs for hospitals, we developed a continuous, non-invasive, transdermal, auto-calibrating probe monitoring glucose from passive diffusion. The skin of extreme and very preterm neonates is highly permeable allowing the largely unhindered passage of glucose. Hence glucose passively diffuses through the skin to a sensor where its concentration is measured. The measured diffusion rate is proportional to blood glucose. Yet, it depends on the diffusion resistance of the skin, which varies as a function of location, skin type, biophysical and biochemical properties of the skin as well as the age of the infant. We demonstrated the theoretical feasibility of two different approaches measuring glucose transdermally without calibration to take into account the skin permeability. We discarded the first approach consisting of probe with a non-responsive membrane and a very shallow diffusion chamber probed by evanescent wave spectroscopy for fast diffusion reaching equilibrium with blood glucose. The reasons were the insufficient in-vitro accuracy and limitations in miniaturization potential of NIR evanescent wave spectroscopy. Therefore we selected the promising second approach of measuring blood glucose transdermally with differential microdialysis measurement for auto-calibration. This novel noninvasive principle measures two different glucose diffusion rates with two distinct known membrane permeabilities. Therefore, it allows determining the two unknowns, the blood glucose and the skin permeability to glucose. Following this principle, we designed, manufactured, and characterized a microdialysis probe with two separate diffusion chambers, each with a distinct membrane, under the assumption that the skin permeability is locally constant. This probe is dedicated to NICU. It benefits from the properties of its Amphiphilic Polymer Co-Network (APCN) membranes with permeabilities fine-tuned to an acceptable measurement error and advantageous fluidics haracteristics. In addition, we designed, fabricated, and characterized an inline continuous micro-fluorimeter implementing the gold standard of glucose concentration measurement with hexokinase. This fluorimeter renders the microdialysis probe continuous with a small delay of one minute only. Onto a single chamber microdialysis probe, we further bonded an APCN membrane made light responsive with the copolymerization of spiropyran into the membrane hydrophilic nanophase. We demonstrated a significant microdialysate extraction fraction switch in response to UV or visible light illumination. Unfortunately, we showed that this switch is probably only indirect and is induced by temperature changes. This membrane would not allow implementing our non-invasive principle, but showed that other type of membranes with the correct mechanism could do it. But this approach is probably not necessary with the simpler parallel microdialysis chambers design. To the best of our knowledge, this is the first time that such a non-invasive, continuous, auto-calibrated measurement principle is proposed for blood glucose and also implemented with a probe dedicated to extreme and very preterm neonates.

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Additional indexing

Item Type:Dissertation
Referees:Rudin Markus, Wolf Martin, Seitz Peter
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Neonatology
Dewey Decimal Classification:610 Medicine & health
Uncontrolled Keywords:NICU, preterm neonate, blood glucose, glycemia management, transdermal, microdialysis, auto-calibrated, continuous, APCN, membrane
Language:English
Date:2016
Deposited On:25 Jul 2016 13:04
Last Modified:25 Jul 2016 14:11
Number of Pages:232
ISBN:978-3-906327-39-6
Funders:SNF
Official URL:http://e-collection.library.ethz.ch/eserv/eth:49341/eth-49341-01.pdf
Permanent URL: https://doi.org/10.5167/uzh-125067

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